Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer death in the USA and one of the deadliest cancers. Our clinical trials demonstrate that screening individuals with an inherited predisposition to pancreatic cancer is effective at identifying pre-invasive neoplasms that can be cured by surgical resection. Markers are needed to improve the ability of screening to detect pancreatic neoplasia. Although pancreatic imaging can identify most pancreatic cancers and IPMNs, it cannot identify microscopic high-grade pancreatic intraepithelial neoplasias (PanINs). Since resecting high-grade PanIN can be curative, accurate markers detectable in pancreatic fluids are needed to identify these lesions. Advances in our ability to detect low concentrations of mutant DNA are making this feasible. Developing methods to safely collect pure pancreatic fluids would likely improve the diagnostic accuracy of markers of pancreatic neoplasia. In addition to markers for early detection, better markers to identify minimal residual disease, tumor recurrence and tumor responses to therapy would likely permit earlier and more effective therapeutic interventions. Circulating tumor DNA is one such marker. We have developed highly accurate methods for measuring markers of pancreatic neoplasia. Therefore, we propose: Aim #1: To evaluate somatic mutations and chromosomal alterations as markers of high-grade pancreatic neoplasia in pancreatic juice in patients undergoing pancreatic screening. Specifically: (a) To evaluate somatic mutations (including p53, KRAS, p16), (b): To characterize the chromosomal alterations of intermediate and high-grade PanINs, and (c): To detect chromosomal rearrangements at low-concentration in pancreatic fluids. Aim #2: To evaluate pure pancreatic juice as a source of markers of pancreatic neoplasia: Specifically: a) To design an endoscopic pancreatic juice collection catheter, b): To compare the mutational profiles of pure pancreatic juice with those of pancreatic juice collected In the duodenum. Aim #3: To evaluate circulating tumor DNA (ctDNA) as a marker of tumor burden in patients with pancreatic cancer including a): as a measure of minimal residual disease and predictor of early recurrence, and b): as a measure of tumor response to therapy.